Systemic Macrophage Depletion Inhibits Helicobacter bilis-Induced Proinflammatory Cytokine-Mediated Typhlocolitis and Impairs Bacterial Colonization Dynamics in a BALB/c
            <i>Rag2</i>
            <sup>−/−</sup>
            Mouse Model of Inflammatory Bowel Disease

Muthupalani, Sureshkumar; Ge, Zhongming; Feng, Yan; Rickman, Barry; Mobley, Melissa W.; McCabe, Amanda; Rooijen, Nico van; Fox, James G.

doi:10.1128/iai.00530-12

Cited by 25 publications

(19 citation statements)

References 51 publications

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“…TLR4m mice had markedly decreased levels of iNOS mRNA expression, which is also consistent with decreased activation of macrophages in other models of inflammation. 23, 29 The decreased activation of the NF-κβ pathway indicates that the TLR4 receptor MyD88-dependent pathway likely modulates the NF-κβ pathway activity during reperfusion injury. As expected, the decrease in NF-κβ expression was associated with increased IkBα expression, which suggests that the decrease in NF-κB is not a nonspecific event.…”

Section: Discussionmentioning

confidence: 99%

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Öklü¹,

Albadawi²,

Jones³

et al. 2013

Journal of Vascular Surgery

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Objective Ischemia-reperfusion (IR) injury is a significant problem in the management of patients with acute limb ischemia (ALI). Despite rapid restoration of blood flow following technically successful open and endovascular revascularization, complications secondary to IR injury continue to occur and limit clinical success. Our aim was to create a murine model of hind limb IR injury to examine the role of Toll-like receptor-4 (TLR4) and to determine whether inactive TLR4 led to a decrease in the detection of neutrophil extracellular traps (NETs), which is known to be highly thrombogenic and may mediate microvascular injury. Methods A calibrated tension tourniquet was applied to unilateral hind limb of wild type (WT) and TLR4 receptor mutant (TLR4m) mice for 1.5 hours to induce ischemia and then immediately removed to initiate reperfusion. At the end of 48 hours of reperfusion, mice were sacrificed and hind limb tissue as well as serum specimens were collected for analysis. Hematoxylin and eosin stained sections of hind limb skeletal muscle tissue were examined for fiber injury. For immunohistochemistry, mouse monoclonal anti-histone H2A/H2B/DNA complex antibody to detect NETs and rabbit polyclonal anti-myeloperoxidase (MPO) antibody were used to identify infiltrating cells containing MPO. Muscle ATP levels, nuclear NF-κB activity, IκBα, poly (ADP-ribose) polymerase (PARP) activity and iNOS expression were measured. Systemic levels of KC, MCP-1 and VEGF in the serum samples were also examined. Results IR injury in the hind limb of wild type mice demonstrated significant levels of muscle fiber injury, decreased energy substrates, increased NF-κB activation, decreased I-κBα levels, increased iNOS expression and increased PARP activity levels when compared to the TLR4 knockout mice samples. Additionally, there was marked decrease in the level of neutrophil and monocyte infiltration in the TLR4 mutant mice, which corresponded to similar levels of decreased NETs detection in the interstitial space and in microvascular thrombi. In situ nuclease treatment of wild-type tissue sections significantly diminished the level of NETs immunostaining demonstrating the specificity of our antibody to detect NETs and suggesting a potential role for nuclease treatment in IR injury. Conclusions These results suggest a pivotal role for TLR4 in mediating hind limb IR injury and suggest that NETs may contribute to muscle fiber injury.

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Section: Discussionmentioning

confidence: 99%

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Öklü¹,

Albadawi²,

Jones³

et al. 2013

Journal of Vascular Surgery

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“…After Cl 2 exposure, we measured respiratory system mechanics in response to inhaled methacholine (MCh) and assessed airway inflammatory cell profiles, proinflammatory cytokine levels, antioxidant gene expression, and nuclear factor (erythroid-derived 2)-like 2 (NRF-2) epithelial cell nuclear translocation in vivo and in vitro. We also assessed the independent contribution of eosinophils and macrophages in the induction of Cl 2 -induced AHR and inflammation using an anti-IL-5 antibody (30) or intratracheal and systemic administration of clodronate liposomes (31)(32)(33), respectively.…”

Section: Clinical Relevancementioning

confidence: 99%

Neutrophils Mediate Airway Hyperresponsiveness after Chlorine-Induced Airway Injury in the Mouse

McGovern

Goldberger²,

Allard³

et al. 2015

Am J Respir Cell Mol Biol

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Chlorine gas (Cl2) inhalation causes oxidative stress, airway epithelial damage, airway hyperresponsiveness (AHR), and neutrophilia. We evaluated the effect of neutrophil depletion on Cl2-induced AHR and its effect on the endogenous antioxidant response, and if eosinophils or macrophages influence Cl2-induced AHR. We exposed male Balb/C mice to 100 ppm Cl2 for 5 minutes. We quantified inflammatory cell populations in bronchoalveolar lavage (BAL), the antioxidant response in lung tissue by quantitative PCR, and nuclear factor (erythroid-derived 2)-like 2 (NRF2) nuclear translocation by immunofluorescence. In vitro, NRF2 nuclear translocation in response to exogenous hypochlorite was assessed using a luciferase assay. Anti-granulocyte receptor-1 antibody or anti-Ly6G was used to deplete neutrophils. The effects of neutrophil depletion on IL-13 and IL-17 were measured by ELISA. Eosinophils and macrophages were depleted using TRFK5 or clodronate-loaded liposomes, respectively. AHR was evaluated with the constant-phase model in response to inhaled aerosolized methacholine. Our results show that Cl2 exposure induced neutrophilia and increased expression of NRF2 mRNA, superoxide dismutase-1, and heme-oxygenase 1. Neutrophil depletion abolished Cl2-induced AHR in large conducting airways and prevented increases in antioxidant gene expression and NRF2 nuclear translocation. Exogenous hypochlorite administration resulted in increased NRF2 nuclear translocation in vitro. After Cl2 exposure, neutrophils occupied 22 ± 7% of the luminal space in large airways. IL-17 in BAL was increased after Cl2, although this effect was not prevented by neutrophil depletion. Neither depletion of eosinophils nor macrophages prevented Cl2-induced AHR. Our data suggest the ability of neutrophils to promote Cl2-induced AHR is dependent on increases in oxidative stress and occupation of luminal space in large airways.

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“…Clodronate-treated mice exhibited significantly lower histopathology scores and suppressed expression of macrophage-related factors, such as TNF-α, Il-1β, and iNOS, suggesting that macrophages are important mediators of H. bilis -induced colitis. However, the finding that clodronate treatment concomitantly reduced the number of MPO-positive neutrophils suggests that both macrophages and neutrophils closely interact in disease development on a functional level [41]. This view is supported by the H. hepaticus Rag2 −/− mouse model that revealed cytokine signatures suggestive of both neutrophil and macrophage activity [29].…”

Section: Immunological Chemistry Of Inflammatory Bowel Diseasementioning

confidence: 99%

“…In the inflamed gut, iNOS is present throughout the intestinal tract, including the jejunum and colon [26,27,33,37,77,78]. Induction of iNOS is regulated by neutrophils and macrophages in combination with cytokine stimuli, as suggested by the fact that depletion of Gr-1 + neutrophils, clodronate-induced depletion of macrophages, and blocking of TNF-α in the colon, respectively, prevented iNOS induction [26,41]. Various mouse studies demonstrated that colitis-induced activation of iNOS is accompanied by increased levels of NO-derived species in plasma and urine [26,38,39,79].…”

Section: Immunological Chemistry Of Inflammatory Bowel Diseasementioning

confidence: 99%

Chemistry meets biology in colitis-associated carcinogenesis

Mangerich

Dedon

Fox

et al. 2013

Free Radical Research

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The intestine comprises an exceptional venue for a dynamic and complex interplay of numerous chemical and biological processes. Here, multiple chemical and biological systems, including the intestinal tissue itself, its associated immune system, the gut microbiota, xenobiotics, and metabolites meet and interact to form a sophisticated and tightly regulated state of tissue homoeostasis. Disturbance of this homeostasis can cause inflammatory bowel disease (IBD) – a chronic disease of multifactorial etiology that is strongly associated with increased risk for cancer development. This review addresses recent developments in research into chemical and biological mechanisms underlying the etiology of inflammation-induced colon cancer. Beginning with a general overview of reactive chemical species generated during colonic inflammation, the mechanistic interplay between chemical and biological mediators of inflammation, the role of genetic toxicology and microbial pathogenesis in disease development are discussed. When possible, we systematically compare evidence from studies utilizing human IBD patients with experimental investigations in mice. The comparison reveals that many strong pathological and mechanistic correlates exist between mouse models of colitis-associated cancer, and the clinically relevant situation in humans. We also summarize several emerging issues in the field, such as the carcinogenic potential of novel inflammation-related DNA adducts and genotoxic microbial factors, the systemic dimension of inflammation-induced genotoxicity, and the complex role of genome maintenance mechanisms during these processes. Taken together, current evidence points to the induction of genetic and epigenetic alterations by chemical and biological inflammatory stimuli ultimately leading to cancer formation.

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Systemic Macrophage Depletion Inhibits Helicobacter bilis-Induced Proinflammatory Cytokine-Mediated Typhlocolitis and Impairs Bacterial Colonization Dynamics in a BALB/c Rag2 ^−/− Mouse Model of Inflammatory Bowel Disease

Cited by 25 publications

References 51 publications

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Neutrophils Mediate Airway Hyperresponsiveness after Chlorine-Induced Airway Injury in the Mouse

Chemistry meets biology in colitis-associated carcinogenesis

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Systemic Macrophage Depletion Inhibits Helicobacter bilis-Induced Proinflammatory Cytokine-Mediated Typhlocolitis and Impairs Bacterial Colonization Dynamics in a BALB/c Rag2 −/− Mouse Model of Inflammatory Bowel Disease

Cited by 25 publications

References 51 publications

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Reduced hind limb ischemia-reperfusion injury in Toll-like receptor-4 mutant mice is associated with decreased neutrophil extracellular traps

Neutrophils Mediate Airway Hyperresponsiveness after Chlorine-Induced Airway Injury in the Mouse

Chemistry meets biology in colitis-associated carcinogenesis

Contact Info

Product

Resources

About

Systemic Macrophage Depletion Inhibits Helicobacter bilis-Induced Proinflammatory Cytokine-Mediated Typhlocolitis and Impairs Bacterial Colonization Dynamics in a BALB/c Rag2 ^−/− Mouse Model of Inflammatory Bowel Disease